DESCRIPTION: The use of light to trigger a highly localized release of drugs is promising but with the exception of treatment of tissues that can be irradiated with light directly, photo-triggered drug release is hindered by the extremely limited transmission through tissues of wavelengths outside of the near-infrared window, between approximately 650 - 1300 nm. Photolabile moieties that absorb light efficiently in this window are nearly non-existent, and state-of-the-art approaches to access this window for triggered delivery, such as photothermal heating of nanoparticles or two-photon absorption of photocleavable linkers, use light inefficiently and therefore have highly limited effective penetration depths, even with powerful light sources. Our long-term goal is to develop photolabile triggered-release material platforms that are useful for the on- demand release of drugs. The objective of this application is to develop a new materials approach to phototriggered guest delivery that uses tissue-penetrant light to release trapped guests. Our central hypothesis, based on both previous works in our laboratory and literature precedent, is that hydrogels with alkoxyacene-based cross linkers will decompose upon photosensitization of singlet oxygen (1O2) with wavelengths greater than 650 nm, and that nanoparticles of these materials will enable efficient light- induced release of guests. The rationale of this project is that such materials will harness an efficient, red light-driven photophysical process that is already FDA-approved-1O2 photosensitization-to cause photoinduced release of therapeutics. Prof. Samuel Thomas is a recognized expert in the two areas where this application intersect-i) photolabile polymeric materials and ii) the reactions of photogenerated 1O2 with acenes, while Prof. Qiaobing Xu is an expert in nanomedicine and drug delivery. We will test our central hypothesis and accomplish our objective by pursuing the following Specific Aims: 1. Degrade macroscopic hydrogels with cross linkers containing alkoxylated acenes induced by 1O2 photogenerated with wavelengths ? 650 nm; 2. Release the drug doxorubicin from 1O2-labile nanogels. This application is innovative, as it is circumvents the inefficiencies inherent to current approaches to accessing the biological NIR window. We expect that our approach will yield the following outcomes: i) new material platforms that decompose on demand upon photogeneration of 1O2, ii) a series of acene-based moieties that span a broad range of reactivity in 1O2-induced bond cleavage, and iii) nanoparticles that release cargo into free solution upon irradiation with tissue-penetrant red or near-infrared light. This study, along with subsequent long-term studies, will have an important positive impact by increasing the efficacy of photo-induced therapeutic delivery, which will mitigate both off-target effects of the delivered drugs through spatial and temporal control, as well as side effects of irradiation itself. The proposed research is significant because it will enable spatially-selective triggered drug release deeper into tissues than is currently achievable.